Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells
Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells
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DOI：
10.1021/tx300376h
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发表时间：
2012-11-01
影响因子：
4.1
通讯作者：
Luparello, Claudio
中科院分区：
文献类型：
--
作者：
Librizzi, Mariangela;Longo, Alessandra;Luparello, Claudio
组蛋白脱乙酰酶抑制剂(HDACis)是一类化学上多相的抗癌药物，琥珀酰苯胺异羟肟酸(SAHA)是其中的典型成员。SAHA衍生物E.0可以通过对SaHA芳基帽子的三维操作来获得，例如掺入二茂铁单元，如Jay Amin异羟肟酸(Jaha)和Homo-Jaha[Spencer等人]中存在的那样。(2011)ACS Med.化学。让我们来吧。2,358-362]。这些基于金属的SAHA类似物已经被测试了它们对三阴性MDA-MB231乳腺癌细胞的细胞毒活性。结果表明，在所测试的两个化合物中，只有JAHA对乳腺癌细胞有显著的抑制作用，作用72小时的IC50为8.45微米。生物学检测显示，HDACI可导致MDAMB231细胞周期紊乱，S期进入改变，G(2)/M期转换延迟，早期活性氧产生，线粒体膜电位消散，自噬抑制。在短期(5h)和较长时间(24和48h)与Jaha孵育后，没有观察到膜联蛋白结合，从而排除了HDACi促进细胞凋亡的作用。尽管必须谨慎地将体外结果外推到需要进行动物研究和人体试验的体内情况，但Jaha治疗具有作为预防和/或治疗“侵袭性”乳腺癌的药物的潜力，从而促使我们更深入地了解其抗乳腺癌活性的分子基础。
The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide 0 hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives e. 0 may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [Spencer, et al. (2011) ACS Med. Chem. Lett. 2, 358-362]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC50 of 8.45 mu M at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G(2)/M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short- (5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of "aggressive" breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity.